title: Tuning the antibacterial activity of amphiphilic neamine derivatives and comparison to paromamine homologues.
abstract: Aminoglycosides are antibiotic drugs that act through binding to rRNA. In the search for antimicrobial amphiphilic aminoglycosides targeting bacterial membranes, we report here on the discovery of three dialkyl derivatives of the small aminoglycoside neamine active against susceptible and resistant Gram-positive and Gram-negative bacteria. One of these derivatives (R = 2-naphthylpropyl), which has good activity against MRSA and VRSA, showed a low toxicity in eukaryotic cells at 10 μM. The synthesis of amphiphilic paromamine and neamine homologous derivatives pointed out the role of the 6'-amine function of the neamine core in the antibacterial effects. The optimal number of lipophilic substituents to be attached to the neamine core and the corresponding required lipophilicity determined here should permit a more selective targeting of bacterial membranes relative to eukaryotic membranes. This work revealed the existence of windows of lipophilicity necessary for obtaining strong antibacterial effects that should be of interest in the field of antibacterial amphiphilic aminoglycosides.
authors.affiliation: Département de Pharmacochimie Moléculaire, Université de Grenoble I/CNRS , UMR 5063, ICMG FR 2607, 470 rue de la Chimie, BP 53, F-38041 Grenoble, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Zimmermann
authors.forename: Antoine
authors.initials: A
authors.lastname: Bussière
authors.forename: Myriam
authors.initials: M
authors.lastname: Ouberai
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baussanne
authors.forename: Claude
authors.initials: C
authors.lastname: Jolivalt
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Mingeot-Leclercq
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Décout
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D005601:Framycetin / Q000737:chemistry* / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D009281:Naphthalenes; D005601:Framycetin; C005936:paromamine; C488396:neamine